This invention relates to compositions and methods for enhancing angiogenesis. More particularly, the invention relates to the use of the Mts-1 gene or Mts-1 protein for enhancing angiogenesis in human and animal subjects.
Angiogenesis is a process by which new blood vessels are generated into a tissue or organ. Angiogenesis in rarely observed in normal tissues in humans and animals. Angiogenic factors from pathological tissues of various kinds have been characterized and isolated, such as those from solid tumors (Folkman et al. J. Exp. Med. 133: 275, 1971), from synovial fluid (Brown et al., Lancet I: 682:685, 1980), from human mayocardial infarcts (Kumar et al., Lancet II: 364-367, 1983), from the vitreous fluid of humans with diabetic retinopathy and in the retinas of animals (Hill et al., Experientia 39: 583-585, 1983; D. Amore et al., Proc. Natl. Acad. Sci. USA 78: 3068-3073, 1981; Kissun et al., Br. J. Ophth. 66: 165-169, 1982), and from wound fluid (Branda et al., Proc. Natl. Acad.Sci. USA 79: 7773-7777, 1982).
Endothelial cells and pericytes, surrounded by a basement membrane, form capillary blood vessels. Angiogenesis begins with the erosion of the basement membrane by enzymes released from endothelial cells and leukocytes. The endothelial cells, which line the lumen of blood vessels, then protrude through the basement membrane. Angiogenic stimulants induce the endothelial cells to migrate through the eroded basement membrane. The migrating cells formula xe2x80x9csproutxe2x80x9d off the parent blood vessel, where the endothelial cells undergo mitosis and proliferate. Eventually, the endothelial sprouts merge with each other to form capillary loops, creating the new blood vessel.
For a general review of angiogenisis, see Maciag, T., Molecular and Cellular Mechanisms of Angiogenesis, in IMPORTANT ADV. ONCOL., pp. 85-98, 1990.
Mouse, rat and human Mts-1 genes have been previously identified and isolated (Linzer et al., Proc. Natl. Acad.Sci. USA 80: 4271-4275, 1983, Barraclogh et al., J. Mol. Biol. 198: 13-20, 1987 and U.S. Pat. No. 5,798,257 to Zain et al.). The Mts-1 protein, as a calcium binding protein, is believed to have a role in cell growth and myoepithelial cell differentiation. U.S. Pat. No. 5,798,257 discloses that the mammalian Mts-1 gene is expressed at 10-100 fold higher levels in metastatic cells compared to non-metastatic cells and normal cells, and thus, that an increased expression of the Mts-1 gene within a cell or tissue is diagnostic of metastatic cancer. The role of Mts-1 in angiogenesis has not been reported prior to the present invention.
The present inventors have uniquely identified that the Mts-1 protein stimulates angiogenesis. Accordingly, the present invention is directed to the use of angiogenic Mts-1 components in therapeutic compositions and methods for enhancing angiogenesis in a subject in need thereof.
The therapeutic compositions and methods of the present invention are useful for any situations in which angiogenesis is inadequate and is clinically required, such as damaged tissues or organs, or transplanted tissues or organs. The compositions and methods of the present invention are particularly useful for patients suffering a cardiac condition (e.g., patients after bypass surgery or heart transplant), patients suffering tissue damage in the skin, gastrointestinal tract, urinal tract, as well as a vascular tissues resistant to vascularization such as the knee, the wrist or the joint, patients who have suffered a stroke and any other patients in need of angiogenesis.
An angiogenic composition of the present invention can include an Mts-1 component, e.g., an Mts-1 protein, a functional fragment or analog of an Mts-1 protein, as well as nucleic acid molecules encoding such proteins, fragments or analogs.
Angiogenic compositions of the present invention can suitably include other substances that are appropriate or desirable for angiogenesis. These substances can include any other angiogenic compounds, growth hormones, growth factors, biologically active segments of growth factors, interleukins, polysaccharides, or mixtures thereof.
Angiogenic Mts-1 components suitable for use in the present methods are preferably provided in a pharmaceutically acceptable carrier, such as oils, water, saline solutions, gel, lipids, liposomes, resins, porous matrices, binders, fillers and the like, or combinations thereof.
The angiogenic compositions can be administered to a subject in need of angiogenesis by standard routes, including the oral, ophthalmic, nasal, topical, transdermal, parenteral, intracranial, intracerebral, intraspinal, intravaginal, intrauterine, or rectal route, or by injection or surgical implantation proximate to a preselected tissue or organ site.